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Phospholipase A2-activating protein is associated with a novel form of leukoencephalopathy.

ABSTRACT: Leukoencephalopathies are a group of white matter disorders related to abnormal formation, maintenance, and turnover of myelin in the central nervous system. These disorders of the brain are categorized according to neuroradiological and pathophysiological criteria. Herein, we have identified a unique form of leukoencephalopathy in seven patients presenting at ages 2 to 4 months with progressive microcephaly, spastic quadriparesis, and global developmental delay. Clinical, metabolic, and imaging characterization of seven patients followed by homozygosity mapping and linkage analysis were performed. Next generation sequencing, bioinformatics, and segregation analyses followed, to determine a loss of function sequence variation in the phospholipase A2-activating protein encoding gene (PLAA). Expression and functional studies of the encoded protein were performed and included measurement of prostaglandin E2 and cytosolic phospholipase A2 activity in membrane fractions of fibroblasts derived from patients and healthy controls. Plaa-null mice were generated and prostaglandin E2 levels were measured in different tissues. The novel phenotype of our patients segregated with a homozygous loss-of-function sequence variant, causing the substitution of leucine at position 752 to phenylalanine, in PLAA, which causes disruption of the protein's ability to induce prostaglandin E2 and cytosolic phospholipase A2 synthesis in patients' fibroblasts. Plaa-null mice were perinatal lethal with reduced brain levels of prostaglandin E2 The non-functional phospholipase A2-activating protein and the associated neurological phenotype, reported herein for the first time, join other complex phospholipid defects that cause leukoencephalopathies in humans, emphasizing the importance of this axis in white matter development and maintenance.

SUBMITTER: Falik Zaccai TC

PROVIDER: S-EPMC5841054 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Phospholipase A2-activating protein is associated with a novel form of leukoencephalopathy.

Falik Zaccai Tzipora C TC Savitzki David D Zivony-Elboum Yifat Y Vilboux Thierry T Fitts Eric C EC Shoval Yishay Y Kalfon Limor L Samra Nadra N Keren Zohar Z Gross Bella B Chasnyk Natalia N Straussberg Rachel R Mullikin James C JC Teer Jamie K JK Geiger Dan D Kornitzer Daniel D Bitterman-Deutsch Ora O Samson Abraham O AO Wakamiya Maki M Peterson Johnny W JW Kirtley Michelle L ML Pinchuk Iryna V IV Baze Wallace B WB Gahl William A WA Kleta Robert R Anikster Yair Y Chopra Ashok K AK

Brain : a journal of neurology 20161221 2

Leukoencephalopathies are a group of white matter disorders related to abnormal formation, maintenance, and turnover of myelin in the central nervous system. These disorders of the brain are categorized according to neuroradiological and pathophysiological criteria. Herein, we have identified a unique form of leukoencephalopathy in seven patients presenting at ages 2 to 4 months with progressive microcephaly, spastic quadriparesis, and global developmental delay. Clinical, metabolic, and imaging ...[more]

PMID: 28007986

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Project description:BackgroundB-cell non-Hodgkin's lymphoma (B-NHL) is one of the major complications of primary Sjögren's syndrome (SS). Chronic inflammation and macrophages in SS minor salivary glands have been previously suggested as significant predictors for lymphoma development among SS patients. Lipoprotein-associated phospholipase A2 (Lp-PLA2)-a product mainly of tissue macrophages-is found in the circulation associated with lipoproteins and has been previously involved in cardiovascular, autoimmune, and malignant diseases, including lymphoma.ObjectiveThe purpose of the current study was to investigate the contributory role of Lp-PLA2 in B-NHL development in the setting of primary SS.MethodsLp-PLA2 activity in serum samples collected from 50 primary SS patients with no lymphoma (SS-nL), 9 primary SS patients with lymphoma (SS-L), and 42 healthy controls (HC) was determined by detection of [3H]PAF degradation products by liquid scintillation counter. Moreover, additional sera from 50 SS-nL, 28 SS-L, and 32 HC were tested for Lp-PLA2 activity using a commercially available ELISA kit. Lp-PLA2 mRNA, and protein expression in minor salivary gland (MSG) tissue samples derived from SS-nL, SS-L patients, and sicca controls (SC) were analyzed by real-time PCR, Western blot, and immunohistochemistry.ResultsSerum Lp-PLA2 activity was significantly increased in SS-L compared to both SS-nL and HC by two independent methods implemented [mean ± SD (nmol/min/ml): 62.0 ± 13.4 vs 47.6 ± 14.4 vs 50.7 ± 16.6, p-values: 0.003 and 0.04, respectively, and 19.4 ± 4.5 vs 15.2 ± 3.3 vs 14.5 ± 3.0, p-values: <0.0001, in both comparisons]. ROC analysis revealed that the serum Lp-PLA2 activity measured either by radioimmunoassay or ELISA has the potential to distinguish between SS-L and SS-nL patients (area under the curve [AUC]: 0.8022, CI [95%]: 0.64-0.96, p-value: 0.004 for radioimmunoassay, and AUC: 0.7696, CI [95%]: 0.66-0.88, p-value: <0.0001, for ELISA). Lp-PLA2 expression in MSG tissues was also increased in SS-L compared to SS-nL and SC at both mRNA and protein level. ROC analysis revealed that both MSG mRNA and protein Lp-PLA2 have the potential to distinguish between SS-nL and SS-L patients (area under the curve [AUC] values of 0.8490, CI [95%]: 0.71-0.99, p-value: 0.0019 and 0.9444, CI [95%]: 0.79-1.00, p- value: 0.0389 respectively). No significant difference in either serum Lp-PLA2 activity or MSG tissue expression was observed between SS-nL and HC.ConclusionsLp-PLA2 serum activity and MSG tissue mRNA/protein expression could be a new biomarker and possibly a novel therapeutic target for B-cell lymphoproliferation in the setting of SS.

Project description:Healthy dietary patterns are associated with lower inflammation and cardiovascular disease (CVD) risk and adherence can be measured using diet quality scores. Inflammation is traditionally measured with C-reactive protein (hsCRP), however there is interest in novel pro-inflammatory markers platelet-activating factor (PAF) and lipoprotein-associated phospholipase A2 (Lp-PLA2) that are specifically involved in endothelial dysfunction and inflammation. This cross-sectional study investigated the association between PAF, Lp-PLA2, hsCRP, and six diet scores. One hundred adults (49 ± 13 years, 31% male) with variable CVD risk were recruited. Fasting PAF, Lp-PLA2 and hsCRP and usual dietary intake were measured. Adherence to Dietary Approaches to Stop Hypertension (DASH), Dairy-adjusted DASH, Vegetarian Lifestyle Index, Healthy Eating Index for Australians (HEIFA), Mediterranean Diet Adherence Screener (MEDAS) and PREDIMED-Plus (erMedDiet) scores were calculated. Correlations and multiple regressions were performed. hsCRP, but not PAF, independently correlated with several diet scores. Lp-PLA2 independently correlated with Vegetarian Lifestyle Index only in unadjusted models. A one-point increase in adherence to the DASH Index, the Dairy-adjusted DASH Index and the Vegetarian Lifestyle Index was associated with a 30%, 30%, and 33% reduction in hsCRP levels, respectively. Smaller effects were seen with the other diet scores with a one-point increase in adherence resulting in a 19%, 22% and 16% reduction in hsCRP with HEIFA, MEDAS, erMedDiet scores, respectively. The lack of stronger associations between the novel markers of inflammation and diet scores may be due to confounding by COVID-19 infection and vaccination programs, which prevents any firm conclusion on the relationship between PAF, Lp-PLA2 and healthy dietary patterns. Future research should aim to examine the relationship with these novel markers and healthy dietary patterns in a non-pandemic setting.

Dataset Information

Phospholipase A2-activating protein is associated with a novel form of leukoencephalopathy.

Publications

Phospholipase A2-activating protein is associated with a novel form of leukoencephalopathy.

Similar Datasets

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